Fyn interrupts telomere maintenance in stem cells by phosphorylating menin at tyrosine 603

Abstract: Telomeres protect chromosome ends and determine the proliferative potential of cells. The canonical telomere sequence TTAGGG is synthesized by telomerase holoenzyme, which maintains telomere length in proliferative stem cells. Although the core components of telomerase are well defined, many aspects of telomerase regulation are poorly understood. We report a novel role for the Src family kinase Fyn, which interrupts telomere maintenance in stem cells by negatively regulating telomerase assembly. We determine that Fyn promotes SUMOylation of the scaffold protein menin at lysine 609 (K609) by phosphorylating menin at tyrosine 603 (Y603). We show that K609-SUMOylated menin associates with much greater affinity to the telomerase RNA component (TERC) and interferes with telomerase assembly by preventing dyskerin (DKC1) and H/ACA ribonucleoprotein complex subunit 1 (GAR1) from binding to TERC. Importantly, we find that inhibition of Fyn reduces telomere shortening in human iPSCs and mice harboring mutations for dyskeratosis congenita.